BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice

Masuo Ohno*, Sarah L. Cole, Marina Yasvoina, Jie Zhao, Martin Citron, Robert Berry, John F. Disterhoft, Robert Vassar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

221 Scopus citations

Abstract

Evidence suggests that β-amyloid (Aβ) peptide triggers a pathogenic cascade leading to neuronal loss in Alzheimer's disease (AD). However, the causal link between Aβ and neuron death in vivo remains unclear since most animal models fail to recapitulate the dramatic cell loss observed in AD. We have recently developed transgenic mice that overexpress human APP and PS1 with five familial AD mutations (5XFAD mice) and exhibit robust neuron death. Here, we demonstrate that genetic deletion of the β-secretase (BACE1) not only abrogates Aβ generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum, brain regions manifesting the most severe amyloidosis in 5XFAD mice. Importantly, BACE1 gene deletion also rescues memory deficits in 5XFAD mice. Our findings provide strong evidence that Aβ ultimately is responsible for neuron death in AD and validate the therapeutic potential of BACE1-inhibiting approaches for the treatment of AD.

Original languageEnglish (US)
Pages (from-to)134-145
Number of pages12
JournalNeurobiology of Disease
Volume26
Issue number1
DOIs
StatePublished - Apr 2007

Keywords

  • Alzheimer's disease
  • BACE1 knockout
  • Cognitive impairment
  • Gliosis
  • Spontaneous alternation
  • Tg6799
  • Y-maze
  • β-Amyloid (Aβ)
  • β-Secretase

ASJC Scopus subject areas

  • Neurology

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